APE1 Upregulates MMP-14 via Redox-Sensitive ARF6-Mediated Recycling to Promote Cell Invasion of Esophageal Adenocarcinoma
APE1 Upregulates MMP-14 via Redox-Sensitive ARF6-Mediated Recycling to Promote Cell Invasion of Esophageal Adenocarcinoma
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DOI：
10.1158/0008-5472.can-19-0237
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发表时间：
2019-09-01
期刊：
影响因子：
11.2
通讯作者：
El-Rifai, Wael
中科院分区：
文献类型：
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作者：
Lu, Heng;Bhat, Ajaz A.;El-Rifai, Wael
食道腺癌是一种侵袭性的恶性肿瘤，临床预后差。EAC的发病率在过去的三十年中迅速上升。在这里，我们发现脱嘌呤/脱嘧啶核酸内切酶（APE 1）在EAC细胞系，以及发育不良和EAC患者的样本中过表达。APE 1的下调或其氧化还原功能的抑制显着抑制入侵。过表达的氧化还原缺陷突变体，C65 A，废除了APE 1的proinvasive表型。APE 1通过上调基质金属蛋白酶14（MMP-14）调节侵袭，MMP-14随后激活MMP-2，导致细胞外基质以氧化还原依赖性方式降解。下调APE 1或抑制其氧化还原功能可降低MMP-14蛋白的内吞和再循环速率。APE 1与ARF 6相互作用，ARF 6是MMP-14再循环的关键调节因子，以APE 1-氧化还原依赖性方式维持ARF 6活性，促进其调节MMP-14再循环至细胞表面的能力。总之，这些发现确定了一个新的氧化还原敏感的APE 1-ARF 6-MMP-14信号轴，介导细胞的侵袭在食管carcinogenesization.Significance：这项研究表明氧化应激和食管腺癌的发展和转移行为之间的关联。
Esophageal adenocarcinoma (EAC) is an aggressive malignancy with poor clinical outcome. The incidence of EAC has been rising rapidly in the past three decades. Here, we showed that apurinic/apyrimidinic endonuclease (APE1) is overexpressed in EAC cell lines, and patients' samples of dysplasia and EAC. Downregulation of APE1 or inhibition of its redox function significantly repressed invasion. Overexpression of a redox-defective mutant, C65A, abrogated the proinvasive phenotype of APE1. APE1 regulated invasion via upregulation of matrix metalloproteinase 14 (MMP-14), which subsequently activated MMP-2, leading to degradation of the extracellular matrix in a redox-dependent manner. Downregulation of APE1 or inhibition of its redox function decreased the rate of endocytosis and recycling of MMP-14 protein. APE1 interacted with ARF6, a key regulator of MMP-14 recycling, which maintained ARF6 activity in an APE1-redox-dependent manner, promoting its ability to regulate MMP-14 recycling to the cell surface. Insummary, these findings identify a novel redox-sensitive APE1-ARF6-MMP-14 signaling axis that mediates cellular invasion in esophageal carcinogenesis.Significance: This study demonstrates the association between oxidative stress and the development and metastatic behavior of esophageal adenocarcinoma.